Essentially all brain lymphomas, as well as many peripheral lymphomas, in AIDS patients carry the Epstein- Barr virus (EBV) genome. We hypothesize that therapeutic approaches which specifically target EBV-infected cells for destruction will be useful in treating AIDS-related lymphomas. We recently showed that expression of the cellular transcription factor, XBP-1, with agents that inhibit type II HDACs is sufficient to induce lytic EBV gene transcription. We find that XBP-1 activates the two viral immediate-early (IE) promoters, while type II HDACs directly inhibit BZLF1 transcriptional function. We propose to build upon these discoveries to identify more effective methods for inducing lytic EBV infection in tumor cells with minimal toxicity to normal cells. We have also discovered that very low level lytic EBV gene expression unexpectedly enhances the ability of early-passage lymphoblastoid cell lines to form lymphoproliferative disease in immunodeficient SCID mice, and we showed that this effect is mediated (at least in part) through release of the B-cell growth factor, IL-6. In Aim 1, we will examine how XBP-1 and different HDACs modulate the level of lytic EBV gene expression, and determine if XBP-1 inducing agents can improve lytic induction strategies. In Aim 2, we will determine whether lytic EBV infection enhances, or inhibits, the development of EBV-induced lymphomas in the context of a reconstituted human immune system. In Aim 3, we will determine if T cells directed against lytic viral antigens can enhance the effectiveness of lytic induction therapies, and examine which lytic induction strategies are most effective/least toxic for inhibiting peritoneal lymphomas in SCID mice. Our proposed studies may lead to novel, EBV-based strategies for treating AIDS-related lymphomas. PUBLIC HEALTH RELEVANCE Epstein-Barr virus is an important cause of AIDS-related lymphomas, as well as other types of malignancies. The proposed research will examine how Epstein-Barr virus can be converted from a latent to active form in tumor cells, and whether drugs that can activate the lytic form of virus can be used to treat EBV-positive tumors.